(8/26/10) - Fatty Acid Oxidation
1. Draw a simple diagram linking glycolysis, the TCA cycle, triglyceride breakdown and triglyceride synthesis as seen in the liver. Include some of the major substrates, intermediates, and products such as glycerol, DHAP, fatty acyl CoA, malonyl CoA and acetyl CoA. See handout 2. Outline the 4 steps involved in the synthesis of triglycerides from glycerol-3-phosphate and activated fatty acids. See handout 3. Describe how fatty acids are mobilized from adipose tissue. Epinephrine binds a cell receptor causing adenylate cyclase to turn an ATP into cAMP. cAMP triggers phosphorylation of hormone sensitive lipase, which removes 1 or 3 FA from a triacylglycerol. Remaining FAs are removed by lipases specific for di- and monoacylglycerol. FAs are now mobilized and the glycerol backbone is transported to liver for future triacylglycerol synthesis. 4. Outline the pathway for activation and transport of the fatty acids to the mitochondrion for catabolism. Identify the role of carnitine and the causes and clinical consequences of a non-functioning shuttle system. FAs are activated by fattyacyl-CoA synthetase, which adds a CoA group to the FA. The carnitine shuttle moves FA-CoA into the mitochondrial matrix by detaching a CoA and adding carnitine to the FA (carinitie acyltransferase I); then moving the FA into the matrix with a carrier where the FA will be re-joined with a CoA group by carnitine acyltransferase II. A non-functioning shuttle system would result in inability to use LCFAs as an energy source. This results in myoglobinemia and weakness after exercise. Genetic deficiency in CAT I results in inability to metabolize LCFAs. Liver can not synthesize glucose during fast; fasts can cause severe hypoglycemia, coma, and death. Treatment: avoid fasts and eat diet high in carbs and low in LCFAs--also take carnitine supplement. During FA synthesis, malonyl-CoA is present in the cytosol and inhibits carnitine acyltransferase I to prevent FA metabolism. 5. Outline the sequence of reactions involved in the complete oxidation of odd-chain and even-chain fatty acids in the mitochondrion. See handout Odd chain FAs are broken down by B-oxidation until the last 3 carbon segment (propionyl-CoA), which is converted to succinyl-CoA and entered into the TCA cycle as is. 6. Be aware that the oxidation pathway of unsaturated fatty acids requires additional steps. ok 7. Compare and contrast the metabolism of acetyl CoA in the liver vs. muscle. Liver can make ketone bodies. 8. Be able to calculate the ATP yield from the oxidation of a given saturated fatty acid. 1 NADH, 1 FADH2, and 1 AcCoA per cycle of B-oxidation. 1 AcCoA = 3 NADH, 1 FADH2 and 1 GTP. For palimitic acid (16 carbons) it’s 7 NADH, 7 FADH2, and 8 AcCoA etc etc. to ATP. 9. Explain the rationale for the pathway of ketogenesis and identify the major intermediates and products of this pathway. See handout for ketone body formation 10. Identify the mechanism by which hormonal activation of lipolysis in adipose tissue is coordinated with activation of gluconeogenesis in the liver during fasting. Lipolysis would occur in conjunction with gluconeogenesis during fasting to bring energy to cells during fasting. Incomplete answer 11. Explain why the liver produces ketone bodies during fasting and how and where they are utilized. Name the two major forms of ketone bodies. Outline the major steps in the synthesis and breakdown of ketone bodies. Mitochondria in liver can divert excess AcCoA to ketone production. During fasting, ketone bodies are another source of energy. Ketones can be used as energy by muscles (skeletal and cardiac) and the brain--in these places, they are converted into AcCoA and enter the TCA cycle. See paper handout synthesis and breakdown of ketone bodies 12. Define the terms: ketosis, ketoacidosis, ketonuria and ketonemia. List common causes of these conditions. Understand how the pH of the body is affected in these cases. Summarize the clinical importance of the ratio of acetoacetate to β-hydroxybutyrate. Ketosis and ketonemia refer to the state of elevated levels of ketone bodies in the blood. Ketoacidosis refers to the state of such elevated levels of ketone bodies that blood pH drops below 7.35--excessive degree of ketosis. Ketonuria is when ketone bodies are present in the urine. These conditions are caused by starvation, severe dieting, and diabetes mellitus. Category:MCM Category:Biochemistry